Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene

Cytokine xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Cytokine journal homepage: www.journals.elsevier.com/cytokine

Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene Nicole R. Leitner, Agnieszka Witalisz-Siepracka, Birgit Strobl, Mathias Müller ⇑ Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria

a r t i c l e

i n f o

Article history: Received 21 October 2015 Accepted 29 October 2015 Available online xxxx Keywords: JAK-STAT pathway Cytokine signalling Non-receptor tyrosine kinases Hallmarks of cancer

a b s t r a c t Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which transduces cytokine and growth factor signalling. Analysis of TYK2 loss-of-function revealed its important role in immunity to infection, (auto-) immunity and (auto-) inflammation. TYK2-deficient patients unravelled high similarity between mice and men with respect to cellular signalling functions and basic immunology. Genomewide association studies link TYK2 to several autoimmune and inflammatory diseases as well as carcinogenesis. Due to its cytokine signalling functions TYK2 was found to be essential in tumour surveillance. Lately TYK2 activating mutants and fusion proteins were detected in patients diagnosed with leukaemic diseases suggesting that TYK2 is a potent oncogene. Here we review the cell intrinsic and extrinsic functions of TYK2 in the characteristics preventing and enabling carcinogenesis. In addition we describe an unexpected function of kinase-inactive TYK2 in tumour rejection. Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction The non-receptor tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family consisting of three additional members (JAK1-3). Cytokine binding to and activation of the respective receptor complexes activate JAKs by auto- or transphosphorylation. Subsequently JAKs phosphorylate intracellular receptor chain residues and activate a family of transcription factors termed signal transducers and activators of transcription (STATs, comprised of STAT1-4, STAT5A, STAT5B and STAT6). Phosphorylated STATs re-orientate in their homo- or heterodimeric conformation and translocate into the nucleus to induce specific gene transcription. The resulting gene expression program drives various cellular mechanisms like proliferation, differentiation or death [1,2]. TYK2 was the first JAK family member genetically linked to cytokine, i.e. interferon (IFN) responses [3]. Further analyses of mutant human cells unresponsive to cytokines revealed that all JAKs are major players in signal transduction of cytokines [4–7]. Today it is well established that defined combinations of mono- or multimeric cytokine receptor complexes associated with JAKs and STATs drive the response to cytokines and growth factors [8,9]. The JAK–STAT pathway is evolutionary highly conserved [10]. The most ancient TYK2 orthologs have been identified in fish [11,12]. Gene targeted mice determined the in vivo loss-offunction (LOF) phenotypes for the Jak loci. In contrast to the lethal⇑ Corresponding author. E-mail address: [email protected] (M. Müller).

ity of lack of JAK1 and JAK2 [13–15] and the severe combined immunodeficiency of lack of JAK3 [16,17], TYK2 LOF does not lead to pathology under conventional housing conditions. Only upon immunological challenges Tyk2
/
mice show pathological phenotypes. Tyk2-deficient mice have been reported by three different groups [18–20]. Additionally, a naturally occurring TYK2 mutant B10.D1-H2q/SgJ mouse strain has been discovered [21]. Recently further naturally occurring mutations in SJL/J and SWR/J mouse strains resulting in reduced TYK2 expression have been identified [22]. A floxed mouse model (Tyk2fl/fl) allows cell type-specific deletion of TYK2 [23]. It becomes increasingly evident that JAKs display functions, which are independent of their enzymatic activity and/ or receptor association. Both mouse and human TYK2 have been shown to exert these non-canonical functions [24–27]. The generation of a kinase-inactive TYK2 mouse (Tyk2K923E) enables the investigation of non-canonical TYK2 in vivo [28]. The data from TYK2 LOF and mutant patients increase constantly and underscore the validity of the murine models for the translation into human pathophysiology and clinical settings [29–32]. The biological role of TYK2 has been mainly established in the context of host responses to infectious agents and of (auto-) immune or (auto-)inflammatory diseases [25]. The importance of TYK2 in tumour immunosurveillance has been also established [33]. While the role for other JAKs as drivers in the development of cancer has been intensively studied since many years, the significance of cell intrinsic TYK2 in oncogenesis has been revealed only recently [34,35]. In this review we will shortly recapitulate the structural features of TYK2 and its established functions in immunity and

http://dx.doi.org/10.1016/j.cyto.2015.10.015 1043-4666/Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: N.R. Leitner et al., Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene, Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.10.015

2

N.R. Leitner et al. / Cytokine xxx (2015) xxx–xxx

inflammation. We will focus on novel reports regarding TYK2’s involvement in tumour surveillance and carcinogenesis. 2. TYK2 structure, stability and post-translational modifications TYK2 has been identified more than 25 years ago [36,37]. It is located on chromosome 19 in humans and chromosome 9 in mice. TYK2, as the other JAKs, is a relatively large protein with a molecular weight of 130 kDa. The sequence homology organizes JAKs into seven JAK homology (JH) domains 1–7 [38]. Structurally JAKs consist of four different domains: the N-terminal 4.1, Ezrin, Radixin, Moesin (FERM) domain, the Src homology 2 (SH2) domain, the pseudokinase domain and the C-terminal kinase domain [38,39] (see Fig. 1). The FERM domain (JH7-5 and a part of JH4) mediates stable association of JAKs with receptor domains. So far only shown for JAK2 and JAK3 it is also involved in kinase activity

regulation [40,41]. The SH2 domain (half of JH4 and JH3) is involved in receptor binding [42]. The pseudokinase domain (JH2) has a canonical kinase domain that lacks catalytical function despite binding ATP [43] and is important for regulating the activity of the kinase domain [39,44]. Interestingly, the JAK pseudokinase domain is frequently mutated in human cancer patients [39,44]. The C-terminal kinase domain (JH1) harbours the catalytically active kinase with the two conserved tyrosine residues in the activation loop (see below). So far the molecular mechanism how the JAK pseudokinase regulates the activity of the kinase domain is not fully understood. A recent crystal structure of the kinase/ pseudokinase domains of TYK2 indicates that the pseudokinase domain exerts an autoinhibitory function on the kinase domain, which becomes activated upon receptor dimerization [45,46]. Activation of TYK2 occurs by phosphorylation at Y1054/Y1055 in humans and Y1047/Y1048 in mice [25] (see Fig. 1). Several other

Fig. 1. Schematic TYK2 structure, post-translational modification and mutation sites of TYK2 in mice and men. Upper panel. TYK2 consists of four structural domains ranging from JAK homology (JH) domain 1–7 indicated on top. The amino acid scale of human TYK2 is depicted; murine TYK2 is 1180 aa (www.uniprot.org) in length. Middle panel. Phosphorylation (dark blue) and ubiquitination (light blue) sites in human TYK2 (top) and orthologous residues in murine TYK2 (below) are indicated. Lower panel. Naturally occurring and induced amino acid variants along TYK2 are depicted for humans (top, see Refs. [46,99,106,191,193,199–202]) and mice (bottom, see Refs. [21,22,28]). Mutations resulting in catalytically inactive or impaired TYK2 variants are depicted in blue, catalytically hyperactive TYK2 variants are shown in pink. Missense mutations with so far unknown consequences are illustrated in grey.

Please cite this article in press as: N.R. Leitner et al., Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene, Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.10.015

3

N.R. Leitner et al. / Cytokine xxx (2015) xxx–xxx

amino acid residues (see Fig. 1) have been further reported to undergo phosphorylation on serine or tyrosine, but so far their function is unknown [47–52]. For JAK2 phosphorylation of residues Y119 (FERM domain), S523 and Y570 (SH2/pseudokinase domains) have negative regulatory effects, while phosphorylation of Y813 (pseudokinase domain) has positive regulatory effects [39,53]. So far, no orthologous phosphorylated residues have been identified in TYK2. One case of ubiquitination has so far been identified for TYK2 [54], whereas SUMOylation has only been reported for JAK2 [55] (see Fig. 1). The functions of the posttranslational modifications outside the activation loop are grossly unknown. Equally unknown are the turnover rates of TYK2 in vivo in different tissues and under different activity and/or posttranslational modified states. Early in vitro studies determined an intermediate half-life of TYK2 upon stimulation of approximately two hours [56]. The heat shock family member HSP90 was found to interact with TYK2 thereby stabilizing it [57,58]. Recently pharmaceutical targeting of HSP90 was identified as promising cancer therapy because HSP90 inhibitors lead to degradation of wildtype and constitutively active mutant TYK2 with subsequent impairment of signalling in cell lines and patient samples [59]. C-terminal structure analysis of TYK2 is of high priority because this enables identification of inhibitory molecules [60,61]. Nevertheless additional efforts are required to elucidate the full-length structure of TYK2 (ideally bound to a paradigm receptor) and the imaging-based analysis of TYK2 activities; proof of methodological feasibility has been provided for JAK1 and JAK2 [62,63]. The power of mass spectrometry combined with in vitro/in vivo gene editing [64,65] should be used to decipher the biological significance of the post-translational modifications of TYK2.

Table 1 Cytokines activating TYK2 in association with the respective receptor chains. Cytokine receptor family

Cytokine/growth factor

Class I cytokine receptors gp130 IL-6 receptor family IL-11 CT-1, CLC CNTF LIF OSM IL-27 IL-12 IL-12 receptor family IL-23 IL-13 IL-13 receptors Class II cytokine receptors IFN type I Mainly IFNas and receptors IFNb IL-10 IL-10 receptor family IL-22 IL-26 IFN type III IFNk1-4 receptors

Receptor chain(s) associated with TYK2

Receptor chain(s) associated with other JAKs

gp130/TYK2

IL-6Ra/JAK1,2

gp130/TYK2 gp130/TYK2 gp130/TYK2 gp130/TYK2 gp130/TYK2 gp130/JAK1, TYK2 IL12-Rb1/TYK2

IL-11Ra/JAK1,2 LIFR/JAK1,2 CNTFR/JAK1,2 LIFR/JAK1,2 OSMR/JAK1,2 IL-27R/JAK2 IL12-Rb2/JAK2

IL12-Rb1/TYK2 IL-13Ra/TYK2

IL-23R/JAK2 IL-4Ra/JAK1

IFNAR1/TYK2

IFNAR2/JAK1

IL-10R2/TYK2

IL-10R1/JAK1

IL-10R2/TYK2 IL-10R2/TYK2 IL10-R2/TYK2

IL-22R1/JAK1 IL-20Ra/JAK1 IL28R1/JAK1

Note that we have grouped the cytokines according to their receptor chain compositions. Classification according to the cytokine families would include for the IL6 family IL-31; for the IL-12 family IL-27 and IL-35; for the IL-10 family the subfamilies IL-20 (including IL-19, IL-22, IL-24; IL-26) and the more distantly related IL28 and IL-29 (aka IFNk).

3. Cytokine signalling via TYK2 and (de-)activation of TYK2 TYK2 is expressed ubiquitously and has been shown to be associated with five different receptor chains: IFN a receptor 1 (IFNAR1), interleukin (IL) 10 receptor 2 (IL-10R2), IL-12 receptor b1 (IL-12Rb1), IL-13 receptor a1 (IL-13Ra1) and gp130. JAK1 or JAK2, but never JAK3 are associated to the corresponding second receptor chain of the receptor complex [25] (see Table 1). Accordingly TYK2 is activated, i.e. phosphorylated on the JH1 domain tyrosine residues, upon binding of type I IFNs (IFNas, IFNb and others, see [66,67]), the IL-10/IL-20 (sub)families of cytokines [68,69], the IL-12 family [70], IL-4/IL-13 [71,72] and the IL-6/gp130 family of cytokines [73,74] to the cognate receptor complexes. The dependence of the cellular responses on TYK2 may vary between different cytokines/growth factors and also between mice and men. In summary, data accumulated from LOF of TYK2 cells show profound contributions of TYK2 to signalling of type I and III IFNs, IL-12, IL13, IL-22, and IL-23 [25,75–79]. For the IL-6 family members and IL-10 the biological significance of TYK2 is neglectable or unclear [25,80]. JAKs are negatively regulated by phosphatases and SOCS (suppressors of cytokine signalling) [39]. Expression of SOCS family members is induced via the JAK–STAT pathway in order to act as a negative feedback loop [81,82]. Recently, transcellular delivery of SOCS in exosomes has been reported as alternative counterregulatory mechanism [83]. SOCS proteins exert their functions by induction of degradation of JAK-associated receptor complexes [84]. Out of the 8 SOCS family members SOCS1 and SOCS3 were shown to inhibit TYK2 [85–89]. Src homology 2 domain containing protein tyrosine phosphatase (SHP) 1 directly interacts with TYK2 [90,91]. Protein tyrosine phosphatase (PTP) 1B effectively binds to TYK2 and increased PTP1B inhibits IFN signalling [92,93]. Finally, CD45 is reported to dephosphorylate all JAK family members [94].

4. TYK2 in (auto-) immunity and (auto-) inflammation Many studies utilizing LOF mice revealed the importance of TYK2 in disease with either harmful or beneficial effects. TYK2 is required for immunity to microbial infections mainly through transducing signals of type I IFNs and IL-12. On the other hand TYK2 is detrimental in (auto-) inflammatory and/or (auto- or chronic) immune diseases through amplification and/or prolongation of cytokine responses (for a review see [25]). In 2006 the first patient with a homozygous TYK2 deletion resulting in loss of TYK2 due to a premature stop codon at aa 90 has been described [31]. The patient was diagnosed with autosomal recessive (AR) hyper IgE syndrome (HIES) and suffered from viral, fungal and mycobacterial infections. Screening of other HIES patients revealed that TYK2 deficiency is not a common cause of HIES [95,96]. The patient’s cells showed impaired signalling of type I IFN, IL-6, IL-10, IL-12 and IL-23. Subsequently seven TYK2deficient patients were identified suffering from viral and/or mycobacterial infections but not from HIES, candidiasis or inflammatory diseases. In-depth analyses of signalling pathways and cytokine production profiles showed impaired but not abolished responses to all TYK2 activating cytokines (see Table 1) except to IL-6 [29,30,32]. Several genome-wide association studies (GWAS) emerged in the recent years linking TYK2 to autoimmune and inflammatory diseases [97]. TYK2 polymorphisms have been associated with systemic lupus erythematosus (SLE) [98–102], multiple sclerosis (MS) [103–105], systemic sclerosis (SSc) [106] rheumatoid arthritis (RA) [99,107], Crohn’s disease (CD) and ulcerative colitis (UC) [108,109], psoriasis [107], type I diabetes [110–112], primary biliary cirrhosis (PBC) [113] and idiopathic inflammatory myopathies (IIM) [114].

Please cite this article in press as: N.R. Leitner et al., Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene, Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.10.015

4

N.R. Leitner et al. / Cytokine xxx (2015) xxx–xxx

Future studies will show whether the single nucleotide polymorphisms (SNPs) are causative for or only correlated to these diseases. 5. TYK2 in cancer After the initial reports of mutations in the last century the JAK–STAT pathway gained highest attention through the discovery of the activating JAK2V617F mutation causing myeloproliferative diseases in 2005 [115–118]. Since then next generation sequencing (NGS) led to the rapid identification of many more JAK–STAT mutations. The data revealed that the JAK–STAT pathway is among the most mutated signal transduction pathways in cancer and therefor was coined by Bert Vogelstein as one of the 12 core cancer pathways [119]. Not only does JAK–STAT contribute to most if not all hallmarks of cancer [120–124], it also acts in a cell type-specific and mutational context-dependent fashion to display tumour suppressive as well as oncogenic properties. In the following we summarize the known contributions of TYK2 to the hallmarks and enabling characteristics of cancer (see Table 2) [122,125]. 5.1. ‘Avoiding Immune Destruction’; ‘Tumour Promoting Inflammation’ – Kinase-dependent and -independent functions of TYK2 Immunity and inflammation are central in the initiation, recognition, elimination or prolongation of cancerous transformations [126,127]. Historically, Veronika Sexl’s and our labs were the first to link TYK2 to cancer by transplantable and induced tumours in LOF mice, which developed haematopoietic malignancies due to impaired cytotoxicity of NK and T cells [128,129]. Subsequently we identified an indispensable role of TYK2 in the immune surveillance of adenocarcinoma and T cell lymphoma cells [23,130].

Tumour suppressive functions of TYK2 were also attributed to an inhibitory activity in myeloid-derived suppressor cells keeping the CTLs in check [131]. Anticancer immunity and cytotoxicity is largely shaped by cytokines such as type I IFNs and IL-12 which signal through TYK2 [132–134]. Increasing evidence of kinaseindependent functions of JAKs prompted us to test the hypothesis that some of the defects in immunity against tumours observed in Tyk2
/
mice are independent of the canonical cytokine signalling cascades. To this end, we studied cell mediated tumour immunosurveillance in mice expressing kinase-inactive TYK2 (Tyk2K923E) [28]. Canonical, i.e. kinase-dependent TYK2 activity is required for immunity against viruses in vivo. Moreover, enzyme-inactive TYK2 phenocopied TYK2 LOF with respect to signalling of type I IFNs and IL-12 in NK cells [28,130]. However, NK cell mediated tumour surveillance and cytotoxicity of NK cells remained fully or partially independent of TYK2 catalytic activity [130]. These results reveal that a potential use of TYK2 inhibitors for cancer therapy would not impair the NK cell responses as much as anticipated from studies in LOF mice. Currently we investigate the molecular mechanisms underlying the anti-tumour response of TYK2 kinase-inactive NK cells and whether the phenomenon appears also in other immune cells. The molecular crossroads between cancer and inflammation emerged at the beginning of the new millennium [135,136]. Inflammation may contribute by several mechanisms to tumour development, progression and dissemination by providing growth factors and cytokines that favour proliferation, invasion, angiogenesis and metastasis [137,138]. The involvement of TYK2 in (auto-) inflammatory pathologies is well established in animal models and through GWAS pinpointing TYK2 as an important locus (see above). Currently, the most frequent associations are reported for colitis and colitis-associated cancers [139,140].

5.2. ‘Activating Invasion and Metastasis’; ‘Inducing Angiogenesis’ Table 2 TYK2’s cell extrinsic and intrinsic involvement in the hallmarks and enabling characteristics of cancer. Hallmarks/ characteristics ‘Avoiding Immune Destruction’ ‘Tumour Promoting Inflammation’

‘Inducing Angiogenesis’

Cell extrinsic effects  TYK2 LOF in mice leads to impaired surveillance of B and T cell tumours and of transplantable tumours  TYK2 is detrimental in several mouse models of (auto-) inflammatory diseases  TYK2 is linked to and causative for several human (auto-) immune diseases  TYK2 is essential in uPA-uPAR signalling Cell intrinsic effects

‘Activating Invasion and Metastasis’ ‘Deregulating Cellular Energetics’

   

‘Resisting Cell Death’

 

‘Genome Instability and Mutations’ ‘Enabling Replicative Immortality’ ‘Sustaining Proliferative Signalling’ ‘Evading Growth Suppressors’

 

TYK2 is involved in EMT and expression of MMPs TYK2 drives invasiveness of various cancer types TYK2 is involved in the Warburg effect TYK2 is genetically linked to and/or determines susceptibility to diabetes TYK2 induces and/or interacts with pro-apoptotic factors (e.g. DAXX, SIVA1, TRAIL) TYK2 induces anti-apoptotic genes (e.g. Bcl2, Mcl1) TYK2 mediates autophagy (e.g. through STS1) TYK2 interacts with Ku80

 TYK2 mutations and fusions are oncogenic  TYK2 mutations and fusions are oncogenic

 TYK2 mutations and fusions are oncogenic

Epithelial-to-mesenchymal transition (EMT) is a crucial process facilitating tumour cell invasion and dissemination. Annexin A1 (AnxA1) is frequently downregulated during EMT/metastasis and knockdown of AnxA1 induces EMT in a TYK2-dependent manner [141]. Metalloproteinases (MMPs) also contribute to invasion, metastasis and angiogenesis by degradation of the extracellular matrix (ECM) [142,143]. In an ischemia/reperfusion (I/R) model TYK2 was essential for the expression of MMP-2, 9 and 14 in the intestine [144]. TYK2’s significance in tumour cell dissemination is obviously context-dependent. In an El-Myc transgenic mouse model for human Burkitt’s lymphoma, Tyk2-deficient mice show reduced invasiveness of malignant cells [145]. A similar phenotype was observed with human prostate and breast cancer cells, where inhibition of TYK2 reduced cancer cell invasiveness [57,146]. Hence blocking TYK2 might be an effective therapeutic approach to prevent metastasis. In contrast, TYK2 is frequently downregulated in estrogen receptor alpha (ERa) negative human breast cancer samples during metastasis to the regional lymph node [147]. Angiogenesis is essential to provide the progressive tumour with nutrients and oxygen and involves processes like proteolysis, migration and degradation of the ECM which enable cancer cell invasiveness. The urokinase type plasminogen activator (uPA) and its receptor uPAR coordinate ECM proteolysis and activate signalling pathways leading to cell migration, proliferation and survival [148]. Notably the uPA–uPAR system plays an important role in angiogenesis [149]. Several reports have shown that TYK2 is essential in mediating the uPA–uPAR induced signalling in vascular smooth muscle cells (VSMCs) and glomerular mesangial cells (MCs) [150–155].

Please cite this article in press as: N.R. Leitner et al., Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene, Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.10.015

N.R. Leitner et al. / Cytokine xxx (2015) xxx–xxx

5.3. ‘Deregulating Cellular Energetics’ Analogous to the insight into the molecular communalities between cancer and inflammation a decade ago, recent reports show that the cellular responses upon carcinogenesis and infection share many common features and lead to metabolic changes, best exemplified by aerobic glycolysis also referred to as Warburg effect [124,156,157]. We showed in an early study that TYK2 is required to switch cellular glucose and lipid metabolism during innate immune responses [158]. A comprehensive study suggests that TYK2 dysregulation or LOF leads to obesity [159]. Later, GWAS has linked TYK2 to diabetes susceptibility (see above).

5

promoting senescence and inhibiting stemness [178,179]. For TYK2 an IFN-induced interaction with Ku80 has been reported [180]. The heterodimer Ku70/Ku80 is the main double strand repair pathway in mammals [181]. JAK–STAT signalling is not only involved in the induction and/or activation of the DNA repair molecules but in Drosophila the axis itself was found to remodel chromatin and thereby to stabilise genome regions [182]. Nuclear and chromatin remodelling functions have also been described for mammalian JAKs [183], an exciting field currently intensively investigated. 5.7. ‘Sustaining Proliferative Signalling’; ‘Evading Growth Suppressors’ – TYK2 mutants and fusion proteins in cancers

5.4. ‘Enabling Replicative Immortality’ It is undisputed that cancer cells require unlimited replicative potential in order to form tumours. This capacity centrally involves telomere length and telomerase activity. Non-immortalised cells show almost absent telomerase, hence cell division leads to progressive telomere shortening, which in turn eventually induces senescence and apoptosis. Immortalised cells in contrast express telomerase at functionally significant levels and allow for extension of telomeric DNA [160,161]. Telomerase expression is complex regulated by several transcription factors that are induced by intracellular and extracellular signalling pathways. The multistep molecular regulation of telomerase for differing cell types has to be rigorously elucidated. At least for the development of haematopoietic cancers a cytokine dependent involvement of the JAK–STAT pathway is evident [162]. A specific function of TYK2 remains to be reported. 5.5. ‘Resisting Cell Death’ Preventing apoptosis is a key feature of tumour cells. IFNs are important regulators of apoptosis that induce expression of proor anti-apoptotic genes and disturbed IFN signalling may have fatal effects on cell survival [163,164]. Indeed, the induction of local or tumour-associated IFN-I production is discussed as promising strategy for the induction of cell death [165]. Several studies emphasized the implication of TYK2 in pro- as well as antiapoptotic actions. TYK2 is required for type I IFN induced apoptosis in primary pro-B cells and pancreatic cells [110,166,167]. TYK2 is also essential in IFNa induced B lymphocyte growth arrest or apoptosis by the induction of and/or interaction with pro-apoptotic factors [168,169]. In neuronal cells TYK2 is required for b-amyloid (Ab) induced cell death [170]. TYK2 induces tumour necrosis factor (TNF) related apoptosis inducing ligand (TRAIL) in fibrosarcoma cells [171]. In osteosarcoma cell lines TYK2 has been shown to drive the expression of anti-apoptotic genes like B-cell CLL/lymphoma 2 (BCL2) and myeloid cell leukaemia 1 (MCL1). Furthermore, TYK2 is necessary for cell survival upon fibroblast growth factor (FGF2) signalling [172]. Autophagy may be beneficial or deleterious for tumour cells and IFNs can trigger autophagy [173]. Suppressor of T-cell receptor signalling 1 (STS1) engages the IFNAR/TYK2 axis to induce autophagy in B cells [174]. 5.6. ‘Genome Instability and Mutation’ Mutational signatures of cancer genomes are informative concerning the history and the prognosis of the cancer. The identification of mutational processes may give rise to stratified anticancer therapies [175,176]. Various components of the DNA repair machinery are regulated by transcriptional or post-translational signalling circuits [177]. Recently, type I IFN was found to be directly induced by cytosolic sensing of DNA damage thereby

Cancer cells are most fundamentally characterised by their capability to continuously proliferate. This is typically achieved by gain-of-function (GOF) mutations of proto-oncogenes, LOF of tumour suppressors, loss of negative feedback mechanisms and contact inhibition, GOF mutations of transcription factors and many other mechanisms. Tumour-specific expression or activation profiles of TYK2 have been observed in various cancer types [146,147,184–186]. Reports on mutated and hyperactive TYK2 or inactive TYK2, i.e. oncogenic TYK2 were missing until recently. We screened the COSMIC (catalogue of somatic mutations in cancer; http://cancer.sanger.ac.uk/cosmic) database, which describes over two million coding point mutations in over one million tumour samples across human genes [187,188]. Although over 230 mutations in the TYK2 gene were reported in the database in Q2/2015, this number is far too low for pointing towards accumulating mutations across TYK2, as turned out to be the case for the mutational hotspot in the JH2 domain of JAK2. Nevertheless, the reports on cancer-associated TYK2 mutations increase rapidly [189]. Screening samples from patients suffering from breast or gastrointestinal cancers and acute myeloid leukaemia (AML) a common missense mutation (TYK2P1104A) was identified [190,191]. The mutation is located in the substrate-binding groove of the kinase domain and leads to decreased TYK2 phosphorylation upon IFNa stimulation. Nine additional TYK2 SNPs associated to AML have been described (see Fig. 1) [191]. TYK2V362F emerged also in a screening of 254 established cell lines from brain and haematopoietic tumours [192] as well as in GWAS linking TYK2 to SLE [98]. The first activating (GOF) TYK2 mutations were reported in 2013 by a team headed by A. Thomas Look [193]. Screening of T cell acute lymphoblastic leukaemia (T-ALL) cell lines revealed five variants leading to increased tyrosine phosphorylation of TYK2 (G36D, S47N, V731I, E957D and R1027H in the FERM, the SH2 and the kinase domain; see Fig. 1). The survival of the patient-derived T-ALL cells and of the investigated cell lines was dependent on TYK2 and STAT1. Blocking of TYK2 by inhibitors reduced cell growth in several T-ALL cell lines and primary specimens. This publication drew the community’s attention to TYK2 as a potential oncogene and target for therapeutic kinase inhibitors. All so far identified GOF or LOF and experimentally induced mutations of TYK2 are depicted in Fig. 1. Equally exciting are the recent reports on TYK2 genomic rearrangements identified in three different studies engaging whole genome/transcriptome analysis of patients diagnosed with mature T-cell neoplasms or acute lymphoblastic leukaemia [194–196]. RNA sequencing of a cutaneous T-cell lymphoma-derived cell line revealed a fusion of the 50 region of the nucleophosmin gene (NPM1) with the 30 region of TYK2 including a part of the pseudokinase and the complete kinase domain [196] (see Fig. 2). Extending the study to analysis of a large cohort of mature T-cell lymphoproliferative disorders revealed TYK2 rearrangements in 15% of CD30+ lymphoproliferative disorders (LPDs), amongst them 20% of patients diagnosed with lymphomatoid papulosis (LYP) and

Please cite this article in press as: N.R. Leitner et al., Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene, Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.10.015

6

N.R. Leitner et al. / Cytokine xxx (2015) xxx–xxx

Fig. 2. TYK2 fusion proteins in ALCL and Ph-like ALL. TYK2 fusion proteins with NPM1 (LYP, PC-ALCL), NFKB2 (ALK
ALCL), PABPC4 (ALK
ALCL) and MYB (Ph-like ALL). Fused protein domains in their relative size are shown on top. Gene structures with translated exons (filled boxes) are indicated below. Please note that in accordance with [194] we used exon numbering referring to translated exons, while exon nos. of NPM1-TYK2 and MYB-TYK2 indicated in the original papers [195,196] include non-translated exons. TYK2 domains are indicated: PK (pseudokinase domain) and K (kinase domain). Oncogenic potential has been experimentally shown for NPM1-TYK2 and NFKB-TYK2.

12.5% with primary cutaneous anaplastic large cell lymphoma (PC-ACLC). In total two patients (one LYP and one cutaneous ACLC) carried the described NPM1-TYK2 fusion, whereas the other 5 identified TYK2 rearrangements were not described further. Detailed analysis of the NPM1-TYK2 fusion protein revealed a constitutive TYK2 activation as shown by phosphorylation of Y1054/ Y1055. Interestingly, the subcellular distribution showed that NPM1-TYK2 was localized predominantly in the nucleus. As a consequence of constitutively activated TYK2 also the downstream effectors STAT1, 3 and 5 were constitutively activated by phosphorylation of the respective tyrosine residues. Ectopic expression of a FLAG-tagged NPM1-TYK2 fusion in a HEK293 cell line led to constitutive phosphorylation of TYK2 and STAT1, 3 and 5. This could not be observed when using a kinase-dead TYK2 fusion protein (TYK2K462R). Knockdown of the TYK2 fusion protein by specific small hairpin (sh) RNAs in leukaemic cells led to decreased phosphorylation of STATs and decreased cell proliferation, suggesting that TYK2 is an oncogenic driver kinase. The second report discovered TYK2 fusion proteins in patients diagnosed with anaplastic large cell lymphoma (ALCL) [194]. RNA-Seq of anaplastic lymphoma kinase (ALK)+/ALK
ALCL patients identified 28 fusion proteins amongst them two engaging the C-terminal portion of TYK2. In one case the coding region of exons 1–8 of poly(A) binding protein cytoplasmatic 4 (PABPC4) was fused to exons 14–23 of TYK2 (PABPC4-TYK2) (see Fig. 2). The other case exhibited a fusion of exons 1–16 of nuclear factor of kappa light polypeptide gene enhancer in B cells 2 (NFKB2) to exons 16–23 of TYK2 (NFKB2-TYK2) (see Fig. 2). Ectopic expression of NFKB2-TYK2 in a HEK293 cell line led to constitutive phosphorylation of TYK2, JAK2 and STAT3, which was absent when using

a kinase-dead version of NFKB2-TYK2. The TYK2 fusion protein was localized in both, nucleus and cytoplasm. The oncogenic activity of the fusion protein was proven by transfection of NFKB2-TYK2 into mouse 3T3 fibroblasts, which resulted in a larger number of colonies than in control cells. Interestingly, Stat3
/
murine embryonic fibroblasts (MEF) showed only a slight increase in colonies after transfection of NFKB2-TYK2, suggesting that STAT3 is required for the oncogenic activity of NFKB2-TYK2. Finally the authors revealed that constitutive phosphorylation of STAT1, 3 and 5 could be inhibited by a selective JAK/TYK2 inhibitor and by a specific shRNA when NFKB2-TYK2 was expressed ectopically in MEFs and Jurkat cells. Finally another genomic rearrangement of TYK2 was observed in a patient with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL, also called BCR–ABL1-like ALL). Whole genome and transcriptome sequencing of a cohort of Ph-like ALL patients revealed genomic rearrangements resulting in activated kinase signalling in 96 out of 154 patients [195]. One novel TYK2 fusion protein was identified as a result of a rearrangement of v-myb avian myeloblastosis viral oncogene homolog (MYB) and TYK2. As noted in the two studies described above the TYK2 fusion protein contains a part of the pseudokinase domain and the complete kinase domain (see Fig. 2). Although the authors do not provide any functional analyses, it may be speculated that TYK2 is constitutively active in this case as well and that activated downstream effectors drive the oncogenic activity. Further data on additional patient cohorts and functional analysis of the fusion protein (s) and the activating mutations of TYK2 will further clarify the molecular mechanisms and the frequency of the mutations in leukaemias and other cancers.

Please cite this article in press as: N.R. Leitner et al., Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene, Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.10.015

N.R. Leitner et al. / Cytokine xxx (2015) xxx–xxx

6. Summary and outlook In addition to the well-known function of TYK2 in (auto-) inflammation and immunity to infection and cancers, the recent cancer landscape NGS data revealed the oncogenic potential of TYK2 either as fusion or mutated protein. Working with TYK2 for over two decades sometimes raised the doubt whether TYK2 is a ‘respectable’ member of the JAK kinase family for the following reasons: it was cloned and named differently from JAK1-3; its LOF phenotype is relative subtle compared to the other JAKs; its reported germline or somatic mutations in cancer settings were sparse compared to a plethora of driver mutations in JAK1-3. Now it seems that TYK2 has joined the club of the ’real ones’: the function of TYK2 has expanded from an efficient surveillant of tumours to a bona fide oncogene. Future work will have to show whether the identified activating TYK2 amino acids exchanges and TYK2 fusion proteins are frequent driver or passenger mutations and whether TYK2 inhibitors are efficient anticancer drugs in addition to their current development to treat autoimmune diseases [79,197,198]. Acknowledgement Synthetic analysis of current knowledge and novel concepts proposed in this review were inspired by scientific discussions that arose during the Aegean Conference on Cytokines and Cancer (May 2015, Chania, Greece). BS and MM are supported by the Austrian Science Fund FWF SFB F28 and BS by FWF P 25642-B22. References [1] J.E. Darnell Jr., I.M. Kerr, G.R. Stark, Jak–STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins, Science 264 (1994) 1415–1421. [2] G.R. Stark, J.E. Darnell Jr., The JAK–STAT pathway at twenty, Immunity 36 (2012) 503–514. [3] L. Velazquez, M. Fellous, G.R. Stark, S. Pellegrini, A protein tyrosine kinase in the interferon alpha/beta signaling pathway, Cell 70 (1992) 313–322. [4] P. Macchi, A. Villa, S. Giliani, M.G. Sacco, A. Frattini, F. Porta, et al., Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID), Nature 377 (1995) 65–68. [5] M. Muller, J. Briscoe, C. Laxton, D. Guschin, A. Ziemiecki, O. Silvennoinen, et al., The protein tyrosine kinase JAK1 complements defects in interferonalpha/beta and -gamma signal transduction, Nature 366 (1993) 129–135. [6] S.M. Russell, N. Tayebi, H. Nakajima, M.C. Riedy, J.L. Roberts, M.J. Aman, et al., Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development, Science 270 (1995) 797–800. [7] D. Watling, D. Guschin, M. Muller, O. Silvennoinen, B.A. Witthuhn, F.W. Quelle, et al., Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway, Nature 366 (1993) 166–170. [8] D.E. Levy, J.E. Darnell Jr., Stats: transcriptional control and biological impact, Nat. Rev. Mol. Cell Biol. 3 (2002) 651–662. [9] J.J. O’Shea, R. Plenge, JAK and STAT signaling molecules in immunoregulation and immune-mediated disease, Immunity 36 (2012) 542–550. [10] H. Agaisse, N. Perrimon, The roles of JAK/STAT signaling in Drosophila immune responses, Immunol. Rev. 198 (2004) 72–82. [11] C. Liongue, L.A. O’Sullivan, M.C. Trengove, A.C. Ward, Evolution of JAK–STAT pathway components: mechanisms and role in immune system development, PLoS ONE 7 (2012) e32777. [12] M. Sobhkhez, T. Hansen, D.B. Iliev, A. Skjesol, J.B. Jorgensen, The Atlantic salmon protein tyrosine kinase Tyk2: molecular cloning, modulation of expression and function, Dev. Comp. Immunol. 41 (2013) 553–563. [13] H. Neubauer, A. Cumano, M. Muller, H. Wu, U. Huffstadt, K. Pfeffer, Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis, Cell 93 (1998) 397–409. [14] E. Parganas, D. Wang, D. Stravopodis, D.J. Topham, J.C. Marine, S. Teglund, et al., Jak2 is essential for signaling through a variety of cytokine receptors, Cell 93 (1998) 385–395. [15] S.J. Rodig, M.A. Meraz, J.M. White, P.A. Lampe, J.K. Riley, C.D. Arthur, et al., Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses, Cell 93 (1998) 373–383. [16] T. Nosaka, J.M. van Deursen, R.A. Tripp, W.E. Thierfelder, B.A. Witthuhn, A.P. McMickle, et al., Defective lymphoid development in mice lacking Jak3, Science 270 (1995) 800–802.

7

[17] S.Y. Park, K. Saijo, T. Takahashi, M. Osawa, H. Arase, N. Hirayama, et al., Developmental defects of lymphoid cells in Jak3 kinase-deficient mice, Immunity 3 (1995) 771–782. [18] M. Karaghiosoff, H. Neubauer, C. Lassnig, P. Kovarik, H. Schindler, H. Pircher, et al., Partial impairment of cytokine responses in Tyk2-deficient mice, Immunity 13 (2000) 549–560. [19] K.C. Sheehan, K.S. Lai, G.P. Dunn, A.T. Bruce, M.S. Diamond, J.D. Heutel, et al., Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection, J. Interferon Cytokine Res. 26 (2006) 804–819. [20] K. Shimoda, K. Kato, K. Aoki, T. Matsuda, A. Miyamoto, M. Shibamori, et al., Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function, Immunity 13 (2000) 561–571. [21] M.H. Shaw, V. Boyartchuk, S. Wong, M. Karaghiosoff, J. Ragimbeau, S. Pellegrini, et al., A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity, Proc. Natl. Acad. Sci. USA 100 (2003) 11594–11599. [22] K. Izumi, K. Mine, Y. Inoue, M. Teshima, S. Ogawa, Y. Kai, et al., Reduced Tyk2 gene expression in beta-cells due to natural mutation determines susceptibility to virus-induced diabetes, Nat. Commun. 6 (2015) 6748. [23] R.M. Vielnascher, E. Hainzl, N.R. Leitner, M. Rammerstorfer, D. Popp, A. Witalisz, et al., Conditional ablation of TYK2 in immunity to viral infection and tumor surveillance, Transgenic Res. 23 (2014) 519–529. [24] C.M. Ahmed, H.M. Johnson, The role of a non-canonical JAK–STAT pathway in IFN therapy of poxvirus infection and multiple sclerosis: an example of Occam’s Broom?, JAKSTAT 2 (2013) e26227 [25] B. Strobl, D. Stoiber, V. Sexl, M. Mueller, Tyrosine kinase 2 (TYK2) in cytokine signalling and host immunity, Front. Biosci. (Landmark Ed) 16 (2011) 3214– 3232. [26] G. Uze, G. Schreiber, J. Piehler, S. Pellegrini, The receptor of the type I interferon family, Curr. Top. Microbiol. Immunol. 316 (2007) 71–95. [27] E. Keil, D. Finkenstadt, C. Wufka, M. Trilling, P. Liebfried, B. Strobl, et al., Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation-loop mutation, Blood 123 (2014) 520–529. [28] M. Prchal-Murphy, C. Semper, C. Lassnig, B. Wallner, C. Gausterer, I. TeppnerKlymiuk, et al., TYK2 kinase activity is required for functional type I interferon responses in vivo, PLoS ONE 7 (2012) e39141. [29] S.S. Kilic, M. Hacimustafaoglu, S. Boisson-Dupuis, A.Y. Kreins, A.V. Grant, L. Abel, et al., A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome, J. Pediatr. 160 (2012) 1055–1057. [30] C.S. Ma, N. Wong, G. Rao, D.T. Avery, J. Torpy, T. Hambridge, et al., Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies, J. Allergy Clin. Immunol. 136 (2015) 993–1006. [31] Y. Minegishi, M. Saito, T. Morio, K. Watanabe, K. Agematsu, S. Tsuchiya, et al., Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity, Immunity 25 (2006) 745–755. [32] A.Y. Kreins, M.J. Ciancanelli, S. Okada, X.F. Kong, N. Ramirez-Alejo, S.S. Kilic, et al., Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome, J. Exp. Med. 212 (2015) 1641–1662. [33] C. Ubel, S. Mousset, D. Trufa, H. Sirbu, S. Finotto, Establishing the role of tyrosine kinase 2 in cancer, Oncoimmunology 2 (2013) e22840. [34] J.J. O’Shea, S.M. Holland, L.M. Staudt, JAKs and STATs in immunity, immunodeficiency, and cancer, N. Engl. J. Med. 368 (2013) 161–170. [35] W. Vainchenker, S.N. Constantinescu, JAK/STAT signaling in hematological malignancies, Oncogene 32 (2013) 2601–2613. [36] I. Firmbach-Kraft, M. Byers, T. Shows, R. Dalla-Favera, J.J. Krolewski, Tyk2, prototype of a novel class of non-receptor tyrosine kinase genes, Oncogene 5 (1990) 1329–1336. [37] J.J. Krolewski, R. Lee, R. Eddy, T.B. Shows, R. Dalla-Favera, Identification and chromosomal mapping of new human tyrosine kinase genes, Oncogene 5 (1990) 277–282. [38] A.F. Wilks, A.G. Harpur, R.R. Kurban, S.J. Ralph, G. Zurcher, A. Ziemiecki, Two novel protein-tyrosine kinases, each with a second phosphotransferaserelated catalytic domain, define a new class of protein kinase, Mol. Cell Biol. 11 (1991) 2057–2065. [39] J.J. Babon, I.S. Lucet, J.M. Murphy, N.A. Nicola, L.N. Varghese, The molecular regulation of Janus kinase (JAK) activation, Biochem. J. 462 (2014) 1–13. [40] M. Funakoshi-Tago, S. Pelletier, H. Moritake, E. Parganas, J.N. Ihle, Jak2 FERM domain interaction with the erythropoietin receptor regulates Jak2 kinase activity, Mol. Cell Biol. 28 (2008) 1792–1801. [41] Y.J. Zhou, M. Chen, N.A. Cusack, L.H. Kimmel, K.S. Magnuson, J.G. Boyd, et al., Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases, Mol. Cell 8 (2001) 959–969. [42] H.J. Wallweber, C. Tam, Y. Franke, M.A. Starovasnik, P.J. Lupardus, Structural basis of recognition of interferon-alpha receptor by tyrosine kinase 2, Nat. Struct. Mol. Biol. 21 (2014) 443–448. [43] J.M. Murphy, Q. Zhang, S.N. Young, M.L. Reese, F.P. Bailey, P.A. Eyers, et al., A robust methodology to subclassify pseudokinases based on their nucleotidebinding properties, Biochem. J. 457 (2014) 323–334. [44] O. Silvennoinen, D. Ungureanu, Y. Niranjan, H. Hammaren, R. Bandaranayake, S.R. Hubbard, New insights into the structure and function of the pseudokinase domain in JAK2, Biochem. Soc. Trans. 41 (2013) 1002–1007. [45] P.J. Lupardus, M. Ultsch, H. Wallweber, P. Bir Kohli, A.R. Johnson, C. Eigenbrot, Structure of the pseudokinase-kinase domains from protein kinase TYK2

Please cite this article in press as: N.R. Leitner et al., Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene, Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.10.015

8

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55] [56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65] [66] [67] [68] [69]

[70] [71] [72]

N.R. Leitner et al. / Cytokine xxx (2015) xxx–xxx reveals a mechanism for Janus kinase (JAK) autoinhibition, Proc. Natl. Acad. Sci. USA 111 (2014) 8025–8030. X. Min, D. Ungureanu, S. Maxwell, H. Hammaren, S. Thibault, E.K. Hillert, et al., Structural and functional characterization of the JH2 pseudokinase domain of JAK family tyrosine kinase 2 (TYK2), J. Biol. Chem. (2015), http:// dx.doi.org/10.1074/jbc.M115.672048. pii: jbc.M115.672048 (Epub ahead of print). Y. Bai, J. Li, B. Fang, A. Edwards, G. Zhang, M. Bui, et al., Phosphoproteomics identifies driver tyrosine kinases in sarcoma cell lines and tumors, Cancer Res. 72 (2012) 2501–2511. H. Daub, J.V. Olsen, M. Bairlein, F. Gnad, F.S. Oppermann, R. Korner, et al., Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle, Mol. Cell 31 (2008) 438–448. K. Rikova, A. Guo, Q. Zeng, A. Possemato, J. Yu, H. Haack, et al., Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer, Cell 131 (2007) 1190–1203. T.B. Schreiber, N. Mausbacher, G. Keri, J. Cox, H. Daub, An integrated phosphoproteomics work flow reveals extensive network regulation in early lysophosphatidic acid signaling, Mol. Cell Proteomics 9 (2010) 1047– 1062. T. Shiromizu, J. Adachi, S. Watanabe, T. Murakami, T. Kuga, S. Muraoka, et al., Identification of missing proteins in the neXtProt database and unregistered phosphopeptides in the PhosphoSitePlus database as part of the Chromosome-centric Human Proteome Project, J. Proteome Res. 12 (2013) 2414–2421. H. Zheng, P. Hu, D.F. Quinn, Y.K. Wang, Phosphotyrosine proteomic study of interferon alpha signaling pathway using a combination of immunoprecipitation and immobilized metal affinity chromatography, Mol. Cell Proteomics 4 (2005) 721–730. D. Ungureanu, J. Wu, T. Pekkala, Y. Niranjan, C. Young, O.N. Jensen, et al., The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling, Nat. Struct. Mol. Biol. 18 (2011) 971–976. W. Kim, E.J. Bennett, E.L. Huttlin, A. Guo, J. Li, A. Possemato, et al., Systematic and quantitative assessment of the ubiquitin-modified proteome, Mol. Cell 44 (2011) 325–340. M. Sedek, G.J. Strous, SUMOylation is a regulator of the translocation of Jak2 between nucleus and cytosol, Biochem. J. 453 (2013) 231–239. E. Siewert, W. Muller-Esterl, R. Starr, P.C. Heinrich, F. Schaper, Different protein turnover of interleukin-6-type cytokine signalling components, Eur. J. Biochem. 265 (1999) 251–257. E. Caldas-Lopes, L. Cerchietti, J.H. Ahn, C.C. Clement, A.I. Robles, A. Rodina, et al., Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models, Proc. Natl. Acad. Sci. USA 106 (2009) 8368–8373. M. Taipale, I. Krykbaeva, M. Koeva, C. Kayatekin, K.D. Westover, G.I. Karras, et al., Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition, Cell 150 (2012) 987–1001. K. Akahane, T. Sanda, M.R. Mansour, T. Radimerski, D.J. DeAngelo, D.M. Weinstock, et al., HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia, Leukemia (2015), http://dx.doi.org/10.1038/leu.2015.222 (Epub ahead of print). J. Liang, V. Tsui, A. Van Abbema, L. Bao, K. Barrett, M. Beresini, et al., Lead identification of novel and selective TYK2 inhibitors, Eur. J. Med. Chem. 67 (2013) 175–187. M.A. Argiriadi, E.R. Goedken, D. Banach, D.W. Borhani, A. Burchat, R.W. Dixon, et al., Enabling structure-based drug design of Tyk2 through cocrystallization with a stabilizing aminoindazole inhibitor, BMC Struct. Biol. 12 (2012) 22. P.J. Lupardus, G. Skiniotis, A.J. Rice, C. Thomas, S. Fischer, T. Walz, et al., Structural snapshots of full-length Jak1, a transmembrane gp130/IL-6/IL6Ralpha cytokine receptor complex, and the receptor-Jak1 holocomplex, Structure 19 (2011) 45–55. A.J. Brooks, W. Dai, M.L. O’Mara, D. Abankwa, Y. Chhabra, R.A. Pelekanos, et al., Mechanism of activation of protein kinase JAK2 by the growth hormone receptor, Science 344 (2014) 1249783. J.V. Olsen, M. Mann, Status of large-scale analysis of post-translational modifications by mass spectrometry, Mol. Cell Proteomics 12 (2013) 3444– 3452. J.A. Doudna, E. Charpentier, Genome editing. The new frontier of genome engineering with CRISPR-Cas9, Science 346 (2014) 1258096. S. Pestka, C.D. Krause, M.R. Walter, Interferons, interferon-like cytokines, and their receptors, Immunol. Rev. 202 (2004) 8–32. G. Schreiber, J. Piehler, The molecular basis for functional plasticity in type I interferon signaling, Trends Immunol. 36 (2015) 139–149. S. Rutz, X. Wang, W. Ouyang, The IL-20 subfamily of cytokines – from host defence to tissue homeostasis, Nat. Rev. Immunol. 14 (2014) 783–795. W. Ouyang, S. Rutz, N.K. Crellin, P.A. Valdez, S.G. Hymowitz, Regulation and functions of the IL-10 family of cytokines in inflammation and disease, Annu. Rev. Immunol. 29 (2011) 71–109. D.A. Vignali, V.K. Kuchroo, IL-12 family cytokines: immunological playmakers, Nat. Immunol. 13 (2012) 722–728. S.M. McCormick, N.M. Heller, Commentary: IL-4 and IL-13 receptors and signaling, Cytokine 75 (2015) 38–50. A. Bhattacharjee, M. Shukla, V.P. Yakubenko, A. Mulya, S. Kundu, M.K. Cathcart, IL-4 and IL-13 employ discrete signaling pathways for target gene

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81] [82] [83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

expression in alternatively activated monocytes/macrophages, Free Radic. Biol. Med. 54 (2013) 1–16. C. Garbers, H.M. Hermanns, F. Schaper, G. Muller-Newen, J. Grotzinger, S. Rose-John, et al., Plasticity and cross-talk of interleukin 6-type cytokines, Cytokine Growth Factor Rev. 23 (2012) 85–97. H.M. Hermanns, Oncostatin M and interleukin-31: cytokines, receptors, signal transduction and physiology, Cytokine Growth Factor Rev. 26 (2015) 545–558. E. Hainzl, S. Stockinger, I. Rauch, S. Heider, D. Berry, C. Lassnig, et al., Intestinal epithelial cell tyrosine kinase 2 transduces IL-22 signals to protect from acute colitis, J. Immunol. (2015), http://dx.doi.org/10.4049/jimmunol.1402565. pii: 1402565 (Epub ahead of print). M. Ishizaki, T. Akimoto, R. Muromoto, M. Yokoyama, Y. Ohshiro, Y. Sekine, et al., Involvement of tyrosine kinase-2 in both the IL-12/Th1 and IL-23/Th17 axes in vivo, J. Immunol. 187 (2011) 181–189. M. Ishizaki, R. Muromoto, T. Akimoto, Y. Sekine, S. Kon, M. Diwan, et al., Tyk2 is a therapeutic target for psoriasis-like skin inflammation, Int. Immunol. 26 (2014) 257–267. C.L. Smith, T.L. Arvedson, K.S. Cooke, L.J. Dickmann, C. Forte, H. Li, et al., IL-22 regulates iron availability in vivo through the induction of hepcidin, J. Immunol. 191 (2013) 1845–1855. M.G. Works, F. Yin, C.C. Yin, Y. Yiu, K. Shew, T.T. Tran, et al., Inhibition of TYK2 and JAK1 ameliorates imiquimod-induced psoriasis-like dermatitis by inhibiting IL-22 and the IL-23/IL-17 axis, J. Immunol. 193 (2014) 3278–3287. M. Bosmann, B. Strobl, N. Kichler, D. Rigler, J.J. Grailer, F. Pache, et al., Tyrosine kinase 2 promotes sepsis-associated lethality by facilitating production of interleukin-27, J. Leukoc. Biol. 96 (2014) 123–131. A. Yoshimura, T. Naka, M. Kubo, SOCS proteins, cytokine signalling and immune regulation, Nat. Rev. Immunol. 7 (2007) 454–465. W.S. Alexander, Suppressors of cytokine signalling (SOCS) in the immune system, Nat. Rev. Immunol. 2 (2002) 410–416. E. Bourdonnay, Z. Zaslona, L.R. Penke, J.M. Speth, D.J. Schneider, S. Przybranowski, et al., Transcellular delivery of vesicular SOCS proteins from macrophages to epithelial cells blunts inflammatory signaling, J. Exp. Med. 212 (2015) 729–742. E.M. Linossi, S.E. Nicholson, Kinase inhibition, competitive binding and proteasomal degradation: resolving the molecular function of the suppressor of cytokine signaling (SOCS) proteins, Immunol. Rev. 266 (2015) 123–133. J.J. Babon, N.J. Kershaw, J.M. Murphy, L.N. Varghese, A. Laktyushin, S.N. Young, et al., Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity, Immunity 36 (2012) 239– 250. M. Narazaki, M. Fujimoto, T. Matsumoto, Y. Morita, H. Saito, T. Kajita, et al., Three distinct domains of SSI-1/SOCS-1/JAB protein are required for its suppression of interleukin 6 signaling, Proc. Natl. Acad. Sci. USA 95 (1998) 13130–13134. R.A. Piganis, N.A. De Weerd, J.A. Gould, C.W. Schindler, A. Mansell, S.E. Nicholson, et al., Suppressor of cytokine signaling (SOCS) 1 inhibits type I interferon (IFN) signaling via the interferon alpha receptor (IFNAR1)associated tyrosine kinase Tyk2, J. Biol. Chem. 286 (2011) 33811–33818. H. Sakamoto, H. Yasukawa, M. Masuhara, S. Tanimura, A. Sasaki, K. Yuge, et al., A Janus kinase inhibitor, JAB, is an interferon-gamma-inducible gene and confers resistance to interferons, Blood 92 (1998) 1668–1676. B. Zeng, H. Li, Y. Liu, Z. Zhang, Y. Zhang, R. Yang, Tumor-induced suppressor of cytokine signaling 3 inhibits toll-like receptor 3 signaling in dendritic cells via binding to tyrosine kinase 2, Cancer Res. 68 (2008) 5397–5404. M. David, H.E. Chen, S. Goelz, A.C. Larner, B.G. Neel, Differential regulation of the alpha/beta interferon-stimulated Jak/Stat pathway by the SH2 domaincontaining tyrosine phosphatase SHPTP1, Mol. Cell Biol. 15 (1995) 7050– 7058. A. Yetter, S. Uddin, J.J. Krolewski, H. Jiao, T. Yi, L.C. Platanias, Association of the interferon-dependent tyrosine kinase Tyk-2 with the hematopoietic cell phosphatase, J. Biol. Chem. 270 (1995) 18179–18182. M.P. Myers, J.N. Andersen, A. Cheng, M.L. Tremblay, C.M. Horvath, J.P. Parisien, et al., TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B, J. Biol. Chem. 276 (2001) 47771–47774. X. Zhang, X. Han, Y. Tang, Y. Wu, B. Qu, N. Shen, MiR-744 enhances type I interferon signaling pathway by targeting PTP1B in primary human renal mesangial cells, Sci. Rep. 5 (2015) 12987. J. Irie-Sasaki, T. Sasaki, W. Matsumoto, A. Opavsky, M. Cheng, G. Welstead, et al., CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling, Nature 409 (2001) 349–354. C. Woellner, A.A. Schaffer, J.M. Puck, E.D. Renner, C. Knebel, S.M. Holland, et al., The hyper IgE syndrome and mutations in TYK2, Immunity 26 (2007) 535. author reply 6. T.H. Mogensen, Primary immunodeficiencies with elevated IgE, Int. Rev. Immunol. (2015) 1–18, http://dx.doi.org/10.3109/08830185.2015.1027820 (Epub ahead of print). J.H. Tao, Y.F. Zou, X.L. Feng, J. Li, F. Wang, F.M. Pan, et al., Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases, Mol. Biol. Rep. 38 (2011) 4663–4672. D.S. Cunninghame Graham, D.L. Morris, T.R. Bhangale, L.A. Criswell, A.C. Syvanen, L. Ronnblom, et al., Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus, PLoS Genet. 7 (2011) e1002341. D. Diogo, L. Bastarache, K.P. Liao, R.R. Graham, R.S. Fulton, J.D. Greenberg, et al., TYK2 protein-coding variants protect against rheumatoid arthritis and

Please cite this article in press as: N.R. Leitner et al., Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene, Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.10.015

N.R. Leitner et al. / Cytokine xxx (2015) xxx–xxx

[100]

[101]

[102] [103] [104]

[105]

[106]

[107]

[108]

[109]

[110]

[111]

[112]

[113]

[114]

[115]

[116]

[117]

[118]

[119] [120]

[121] [122] [123] [124] [125] [126]

[127]

[128]

autoimmunity, with no evidence of major pleiotropic effects on nonautoimmune complex traits, PLoS ONE 10 (2015) e0122271. R. Kaiser, L.A. Criswell, Genetics research in systemic lupus erythematosus for clinicians: methodology, progress, and controversies, Curr. Opin. Rheumatol. 22 (2010) 119–125. Y.H. Lee, S.J. Choi, J.D. Ji, G.G. Song, Associations between PXK and TYK2 polymorphisms and systemic lupus erythematosus: a meta-analysis, Inflamm. Res. 61 (2012) 949–954. C. Mohan, C. Putterman, Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis, Nat. Rev. Nephrol. 11 (2015) 329–341. A. Nylander, D.A. Hafler, Multiple sclerosis, J. Clin. Invest. 122 (2012) 1180– 1188. M. Ban, A. Goris, A.R. Lorentzen, A. Baker, T. Mihalova, G. Ingram, et al., Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor, Eur. J. Hum. Genet. 17 (2009) 1309–1313. D.A. Dyment, M.Z. Cader, M.J. Chao, M.R. Lincoln, K.M. Morrison, G. Disanto, et al., Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene, Neurology 79 (2012) 406–411. E. Lopez-Isac, D. Campillo-Davo, L. Bossini-Castillo, S.G. Guerra, S. Assassi, C.P. Simeon, et al., Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway, Ann. Rheum. Dis. (2015), http://dx.doi.org/ 10.1136/annrheumdis-2015-208154. pii: annrheumdis-2015-208154 (Epub ahead of print). T.C. Messemaker, T.W. Huizinga, F. Kurreeman, Immunogenetics of rheumatoid arthritis: understanding functional implications, J. Autoimmun. (2015), http://dx.doi.org/10.1016/j.jaut.2015.07.007. pii: S0896-8411(15) 30010-X (Epub ahead of print). K.M. de Lange, J.C. Barrett, Understanding inflammatory bowel disease via immunogenetics, J. Autoimmun. (2015), http://dx.doi.org/10.1016/ j.jaut.2015.07.013. pii: S0896-8411(15)30014-7 (Epub ahead of print). D. Ellinghaus, E. Ellinghaus, R.P. Nair, P.E. Stuart, T. Esko, A. Metspalu, et al., Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci, Am. J. Hum. Genet. 90 (2012) 636–647. L. Marroqui, R.S. Dos Santos, T. Floyel, F.A. Grieco, I. Santin, A. Op de Beeck, et al., TYK2, a candidate gene for type 1 diabetes, modulates apoptosis and the innate immune response in human pancreatic beta-cells, Diabetes (2015), http://dx.doi.org/10.2337/db15-0362. pii: db150362 (Epub ahead of print). C. Wallace, D.J. Smyth, M. Maisuria-Armer, N.M. Walker, J.A. Todd, D.G. Clayton, The imprinted DLK1–MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes, Nat. Genet. 42 (2010) 68–71. S. Nagafuchi, Y. Kamada-Hibio, K. Hirakawa, N. Tsutsu, M. Minami, A. Okada, et al., TYK2 promoter variant and diabetes mellitus in the Japanese, EBioMedicine 2 (2015) 744–749. J.Z. Liu, M.A. Almarri, D.J. Gaffney, G.F. Mells, L. Jostins, H.J. Cordell, et al., Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis, Nat. Genet. 44 (2012) 1137–1141. M. Jani, J. Massey, L.R. Wedderburn, J. Vencovsky, K. Danko, I.E. Lundberg, et al., Genotyping of immune-related genetic variants identifies TYK2 as a novel associated locus for idiopathic inflammatory myopathies, Ann. Rheum. Dis. 73 (2014) 1750–1752. E.J. Baxter, L.M. Scott, P.J. Campbell, C. East, N. Fourouclas, S. Swanton, et al., Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders, Lancet 365 (2005) 1054–1061. C. James, V. Ugo, J.P. Le Couedic, J. Staerk, F. Delhommeau, C. Lacout, et al., A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera, Nature 434 (2005) 1144–1148. R. Kralovics, F. Passamonti, A.S. Buser, S.S. Teo, R. Tiedt, J.R. Passweg, et al., A gain-of-function mutation of JAK2 in myeloproliferative disorders, N. Engl. J. Med. 352 (2005) 1779–1790. R.L. Levine, M. Wadleigh, J. Cools, B.L. Ebert, G. Wernig, B.J. Huntly, et al., Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis, Cancer Cell 7 (2005) 387–397. B. Vogelstein, N. Papadopoulos, V.E. Velculescu, S.B. Zhou, L.A. Diaz, K.W. Kinzler, Cancer genome landscapes, Science 339 (2013) 1546–1558. M. Buchert, C.J. Burns, M. Ernst, Targeting JAK kinase in solid tumors: emerging opportunities and challenges, Oncogene (2015), http://dx.doi.org/ 10.1038/onc.2015.150 (Epub ahead of print). D. Hanahan, L.M. Coussens, Accessories to the crime: functions of cells recruited to the tumor microenvironment, Cancer Cell 21 (2012) 309–322. D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144 (2011) 646–674. H. Yu, D. Pardoll, R. Jove, STATs in cancer inflammation and immunity: a leading role for STAT3, Nat. Rev. Cancer 9 (2009) 798–809. R.S. Goldszmid, A. Dzutsev, G. Trinchieri, Host immune response to infection and cancer: unexpected commonalities, Cell Host Microbe 15 (2014) 295–305. D. Hanahan, R.A. Weinberg, The hallmarks of cancer, Cell 100 (2000) 57–70. D. Mittal, M.M. Gubin, R.D. Schreiber, M.J. Smyth, New insights into cancer immunoediting and its three component phases – elimination, equilibrium and escape, Curr. Opin. Immunol. 27 (2014) 16–25. R.D. Schreiber, L.J. Old, M.J. Smyth, Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion, Science 331 (2011) 1565–1570. O. Simma, E. Zebedin, N. Neugebauer, C. Schellack, A. Pilz, S. ChangRodriguez, et al., Identification of an indispensable role for tyrosine

[129]

[130]

[131]

[132] [133] [134] [135] [136] [137] [138]

[139] [140]

[141]

[142] [143] [144]

[145]

[146]

[147]

[148] [149]

[150]

[151]

[152]

[153]

[154]

[155]

[156] [157] [158]

9

kinase 2 in CTL-mediated tumor surveillance, Cancer Res. 69 (2009) 203–211. D. Stoiber, B. Kovacic, C. Schuster, C. Schellack, M. Karaghiosoff, R. Kreibich, et al., TYK2 is a key regulator of the surveillance of B lymphoid tumors, J. Clin. Invest. 114 (2004) 1650–1658. M. Prchal-Murphy, A. Witalisz-Siepracka, K.T. Bednarik, E.M. Putz, D. Gotthardt, K. Meissl, et al., In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity, Oncoimmunology 4 (2015) e1047579. Q. Zhang, J.L. Sturgill, M. Kmieciak, K. Szczepanek, M. Derecka, C. Koebel, et al., The role of Tyk2 in regulation of breast cancer growth, J. Interferon Cytokine Res. 31 (2011) 671–677. L. Zitvogel, L. Galluzzi, O. Kepp, M.J. Smyth, G. Kroemer, Type I interferons in anticancer immunity, Nat. Rev. Immunol. 15 (2015) 405–414. S. Zundler, M.F. Neurath, Interleukin-12: functional activities and implications for disease, Cytokine Growth Factor Rev. 26 (2015) 559–568. M.P. Colombo, G. Trinchieri, Interleukin-12 in anti-tumor immunity and immunotherapy, Cytokine Growth Factor Rev. 13 (2002) 155–168. H. Clevers, At the crossroads of inflammation and cancer, Cell 118 (2004) 671–674. L.M. Coussens, Z. Werb, Inflammation and cancer, Nature 420 (2002) 860– 867. S.I. Grivennikov, F.R. Greten, M. Karin, Immunity, inflammation, and cancer, Cell 140 (2010) 883–899. E. Elinav, R. Nowarski, C.A. Thaiss, B. Hu, C. Jin, R.A. Flavell, Inflammationinduced cancer: crosstalk between tumours, immune cells and microorganisms, Nat. Rev. Cancer. 13 (2013) 759–771. M.L. Slattery, A. Lundgreen, The influence of the CHIEF pathway on colorectal cancer-specific mortality, PLoS ONE 9 (2014) e116169. M.L. Slattery, R.K. Wolff, A. Lundgreen, A pathway approach to evaluating the association between the CHIEF pathway and risk of colorectal cancer, Carcinogenesis 36 (2015) 49–59. S. Maschler, C.A. Gebeshuber, E.M. Wiedemann, M. Alacakaptan, M. Schreiber, I. Custic, et al., Annexin A1 attenuates EMT and metastatic potential in breast cancer, EMBO Mol. Med. 2 (2010) 401–414. C.M. Overall, C. Lopez-Otin, Strategies for MMP inhibition in cancer: innovations for the post-trial era, Nat. Rev. Cancer 2 (2002) 657–672. R.E. Vandenbroucke, C. Libert, Is there new hope for therapeutic matrix metalloproteinase inhibition?, Nat Rev. Drug Discov. 13 (2014) 904–927. G. Costantino, M. Egerbacher, T. Kolbe, M. Karaghiosoff, B. Strobl, C. Vogl, et al., Tyk2 and signal transducer and activator of transcription 1 contribute to intestinal I/R injury, Shock 29 (2008) 238–244. C. Schuster, M. Muller, M. Freissmuth, V. Sexl, D. Stoiber, Commentary on H. Ide et al., ‘‘Tyk2 expression and its signaling enhances the invasiveness of prostate cancer cells”, Biochem. Biophys. Res. Commun. 366 (2008) 869–870. H. Ide, T. Nakagawa, Y. Terado, Y. Kamiyama, S. Muto, S. Horie, Tyk2 expression and its signaling enhances the invasiveness of prostate cancer cells, Biochem. Biophys. Res. Commun. 369 (2008) 292–296. Q.X. Sang, Y.G. Man, Y.M. Sung, Z.I. Khamis, L. Zhang, M.H. Lee, et al., Nonreceptor tyrosine kinase 2 reaches its lowest expression levels in human breast cancer during regional nodal metastasis, Clin. Exp. Metastasis 29 (2012) 143–153. H.W. Smith, C.J. Marshall, Regulation of cell signalling by uPAR, Nat. Rev. Mol. Cell Biol. 11 (2010) 23–36. H.C. Kwaan, A.P. Mazar, B.J. McMahon, The apparent uPA/PAI-1 paradox in cancer: more than meets the eye, Semin. Thromb. Hemost. 39 (2013) 382– 391. I. Dumler, A. Kopmann, A. Weis, O.A. Mayboroda, K. Wagner, D.C. Gulba, et al., Urokinase activates the Jak/Stat signal transduction pathway in human vascular endothelial cells, Arterioscler. Thromb. Vasc. Biol. 19 (1999) 290– 297. I. Dumler, A. Weis, O.A. Mayboroda, C. Maasch, U. Jerke, H. Haller, et al., The Jak/Stat pathway and urokinase receptor signaling in human aortic vascular smooth muscle cells, J. Biol. Chem. 273 (1998) 315–321. I. Kiian, N. Tkachuk, H. Haller, I. Dumler, Urokinase-induced migration of human vascular smooth muscle cells requires coupling of the small GTPases RhoA and Rac1 to the Tyk2/PI3-K signalling pathway, Thromb. Haemost. 89 (2003) 904–914. A. Kusch, S. Tkachuk, H. Haller, R. Dietz, D.C. Gulba, M. Lipp, et al., Urokinase stimulates human vascular smooth muscle cell migration via a phosphatidylinositol 3-kinase-Tyk2 interaction, J. Biol. Chem. 275 (2000) 39466–39473. M. Patecki, M. von Schaewen, S. Tkachuk, U. Jerke, R. Dietz, I. Dumler, et al., Tyk2 mediates effects of urokinase on human vascular smooth muscle cell growth, Biochem. Biophys. Res. Commun. 359 (2007) 679–684. N. Shushakova, N. Tkachuk, M. Dangers, S. Tkachuk, J.K. Park, K. Hashimoto, et al., Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor, J. Cell Sci. 118 (2005) 2743– 2753. A.F. McGettrick, L.A. O’Neill, How Metabolism Generates Signals during Innate Immunity and Inflammation, J. Biol. Chem. 288 (2013) 22893–22898. L.A. O’Neill, A broken krebs cycle in macrophages, Immunity 42 (2015) 393– 394. T. Grunert, N.R. Leitner, M. Marchetti-Deschmann, I. Miller, B. Wallner, M. Radwan, et al., A comparative proteome analysis links tyrosine kinase 2

Please cite this article in press as: N.R. Leitner et al., Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene, Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.10.015

10

[159]

[160] [161] [162]

[163] [164] [165]

[166]

[167]

[168]

[169]

[170]

[171]

[172]

[173] [174]

[175] [176] [177] [178]

[179]

[180]

[181]

N.R. Leitner et al. / Cytokine xxx (2015) xxx–xxx (Tyk2) to the regulation of cellular glucose and lipid metabolism in response to poly(I:C), J. Proteomics 74 (2011) 2866–2880. M. Derecka, A. Gornicka, S.B. Koralov, K. Szczepanek, M. Morgan, V. Raje, et al., Tyk2 and Stat3 regulate brown adipose tissue differentiation and obesity, Cell Metab. 16 (2012) 814–824. M.A. Blasco, Telomeres and human disease: ageing, cancer and beyond, Nat. Rev. Genet. 6 (2005) 611–622. Y. Deng, S.S. Chan, S. Chang, Telomere dysfunction and tumour suppression: the senescence connection, Nat. Rev. Cancer 8 (2008) 450–458. O. Yamada, K. Kawauchi, The role of the JAK–STAT pathway and related signal cascades in telomerase activation during the development of hematologic malignancies, JAKSTAT 2 (2013) e25256. H. Cheon, E.C. Borden, G.R. Stark, Interferons and their stimulated genes in the tumor microenvironment, Semin. Oncol. 41 (2014) 156–173. K.P. Kotredes, A.M. Gamero, Interferons as inducers of apoptosis in malignant cells, J. Interferon Cytokine Res. 33 (2013) 162–170. L. Bezu, L.C. Gomes-de-Silva, H. Dewitte, K. Breckpot, J. Fucikova, R. Spisek, et al., Combinatorial strategies for the induction of immunogenic cell death, Front. Immunol. 6 (2015) 187. A.M. Gamero, R. Potla, J. Wegrzyn, M. Szelag, A.E. Edling, K. Shimoda, et al., Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-beta in primary pro-B cells, J. Biol. Chem. 281 (2006) 16238– 16244. R. Potla, T. Koeck, J. Wegrzyn, S. Cherukuri, K. Shimoda, D.P. Baker, et al., Tyk2 tyrosine kinase expression is required for the maintenance of mitochondrial respiration in primary pro-B lymphocytes, Mol. Cell Biol. 26 (2006) 8562– 8571. H.K. Shimoda, K. Shide, T. Kameda, T. Matsunaga, K. Shimoda, Tyrosine kinase 2 interacts with the proapoptotic protein Siva-1 and augments its apoptotic functions, Biochem. Biophys. Res. Commun. 400 (2010) 252–257. K. Shimoda, K. Kamesaki, A. Numata, K. Aoki, T. Matsuda, K. Oritani, et al., Cutting edge: tyk2 is required for the induction and nuclear translocation of Daxx which regulates IFN-alpha-induced suppression of B lymphocyte formation, J. Immunol. 169 (2002) 4707–4711. J. Wan, A.K. Fu, F.C. Ip, H.K. Ng, J. Hugon, G. Page, et al., Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: implications in Alzheimer’s disease, J. Neurosci. 30 (2010) 6873–6881. M.R. Rani, S. Pandalai, J. Shrock, A. Almasan, R.M. Ransohoff, Requirement of catalytically active Tyk2 and accessory signals for the induction of TRAIL mRNA by IFN-beta, J. Interferon Cytokine Res. 27 (2007) 767–779. C.R. Carmo, J. Lyons-Lewis, M.J. Seckl, A.P. Costa-Pereira, A novel requirement for Janus kinases as mediators of drug resistance induced by fibroblast growth factor-2 in human cancer cells, PLoS ONE 6 (2011) e19861. H. Schmeisser, J. Bekisz, K.C. Zoon, New function of type I IFN: induction of autophagy, J. Interferon Cytokine Res. 34 (2014) 71–78. G. Dong, M. You, H. Fan, L. Ding, L. Sun, Y. Hou, STS-1 promotes IFN-alphainduced autophagy by activating the JAK1–STAT1 signaling pathway in B cells, Eur. J. Immunol. 45 (2015) 2377–2388. S. Negrini, V.G. Gorgoulis, T.D. Halazonetis, Genomic instability – an evolving hallmark of cancer, Nat. Rev. Mol. Cell Biol. 11 (2010) 220–228. T. Helleday, S. Eshtad, S. Nik-Zainal, Mechanisms underlying mutational signatures in human cancers, Nat. Rev. Genet. 15 (2014) 585–598. K.K. Biggar, S.S. Li, Non-histone protein methylation as a regulator of cellular signalling and function, Nat. Rev. Mol. Cell Biol. 16 (2015) 5–17. Q. Yu, Y.V. Katlinskaya, C.J. Carbone, B. Zhao, K.V. Katlinski, H. Zheng, et al., DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function, Cell Rep. 11 (2015) 785–797. A. Hartlova, S.F. Erttmann, F.A. Raffi, A.M. Schmalz, U. Resch, S. Anugula, et al., DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity, Immunity 42 (2015) 332–343. L. Adam, D. Bandyopadhyay, R. Kumar, Interferon-alpha signaling promotes nucleus-to-cytoplasmic redistribution of p95Vav, and formation of a multisubunit complex involving Vav, Ku80, and Tyk2, Biochem. Biophys. Res. Commun. 267 (2000) 692–696. V.L. Fell, C. Schild-Poulter, The Ku heterodimer: function in DNA repair and beyond, Mutat. Res. Rev. Mutat. Res. 763 (2015) 15–29.

[182] S. Shi, K. Larson, D. Guo, S.J. Lim, P. Dutta, S.J. Yan, et al., Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability, Nat. Cell Biol. 10 (2008) 489–496. [183] L. Silver-Morse, W.X. Li, JAK–STAT in heterochromatin and genome stability, JAKSTAT 2 (2013) e26090. [184] J. Santos, D. Mesquita, J.D. Barros-Silva, C. Jeronimo, R. Henrique, A. Morais, et al., Uncovering potential downstream targets of oncogenic GRPR overexpression in prostate carcinomas harboring ETS rearrangements, Oncoscience 2 (2015) 497–507. [185] X.C. Song, G. Fu, X. Yang, Z. Jiang, Y. Wang, G.W. Zhou, Protein expression profiling of breast cancer cells by dissociable antibody microarray (DAMA) staining, Mol. Cell Proteomics 7 (2008) 163–169. [186] X. Zhu, J. Lv, L. Yu, X. Zhu, J. Wu, S. Zou, et al., Proteomic identification of differentially-expressed proteins in squamous cervical cancer, Gynecol. Oncol. 112 (2009) 248–256. [187] S.A. Forbes, D. Beare, P. Gunasekaran, K. Leung, N. Bindal, H. Boutselakis, et al., COSMIC: exploring the world’s knowledge of somatic mutations in human cancer, Nucleic Acids Res. 43 (2015). D805-11. [188] S.A. Forbes, N. Bindal, S. Bamford, C. Cole, C.Y. Kok, D. Beare, et al., COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in cancer, Nucleic Acids Res. 39 (2011). D945-50. [189] S. Lee, H.Y. Park, S.Y. Kang, S.J. Kim, J. Hwang, S. Lee, et al., Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type, Oncotarget 6 (2015) 17764–17776. [190] J.S. Kaminker, Y. Zhang, A. Waugh, P.M. Haverty, B. Peters, D. Sebisanovic, et al., Distinguishing cancer-associated missense mutations from common polymorphisms, Cancer Res. 67 (2007) 465–473. [191] M.H. Tomasson, Z. Xiang, R. Walgren, Y. Zhao, Y. Kasai, T. Miner, et al., Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia, Blood 111 (2008) 4797–4808. [192] J.E. Ruhe, S. Streit, S. Hart, C.H. Wong, K. Specht, P. Knyazev, et al., Genetic alterations in the tyrosine kinase transcriptome of human cancer cell lines, Cancer Res. 67 (2007) 11368–11376. [193] T. Sanda, J.W. Tyner, A. Gutierrez, V.N. Ngo, J. Glover, B.H. Chang, et al., TYK2– STAT1–BCL2 pathway dependence in T-cell acute lymphoblastic leukemia, Cancer Discov. 3 (2013) 564–577. [194] R. Crescenzo, F. Abate, E. Lasorsa, F. Tabbo, M. Gaudiano, N. Chiesa, et al., Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma, Cancer Cell 27 (2015) 516–532. [195] K.G. Roberts, Y. Li, D. Payne-Turner, R.C. Harvey, Y.L. Yang, D. Pei, et al., Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia, N. Engl. J. Med. 371 (2014) 1005–1015. [196] T. Velusamy, M.J. Kiel, A.A. Sahasrabuddhe, D. Rolland, C.A. Dixon, N.G. Bailey, et al., A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders, Blood 124 (2014) 3768–3771. [197] S.J. Sohn, K. Barrett, A. Van Abbema, C. Chang, P.B. Kohli, H. Kanda, et al., A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors, J. Immunol. 191 (2013) 2205–2216. [198] J.S. Tokarski, A. Zupa-Fernandez, J.A. Tredup, K. Pike, C. Chang, D. Xie, et al., Tyrosine kinase 2-mediated signal transduction in T lymphocytes is blocked by pharmacological stabilization of its pseudokinase domain, J. Biol. Chem. 290 (2015) 11061–11074. [199] Z. Li, M. Gakovic, J. Ragimbeau, M.L. Eloranta, L. Ronnblom, F. Michel, et al., Two rare disease-associated Tyk2 variants are catalytically impaired but signaling competent, J. Immunol. 190 (2013) 2335–2344. [200] J. Staerk, A. Kallin, J.B. Demoulin, W. Vainchenker, S.N. Constantinescu, JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation: cross-talk with IGF1 receptor, J. Biol. Chem. 280 (2005) 41893– 41899. [201] T.C. Yeh, E. Dondi, G. Uze, S. Pellegrini, A dual role for the kinase-like domain of the tyrosine kinase Tyk2 in interferon-alpha signaling, Proc. Natl. Acad. Sci. USA 97 (2000) 8991–8996. [202] M.C. Gauzzi, L. Velazquez, R. McKendry, K.E. Mogensen, M. Fellous, S. Pellegrini, Interferon-alpha-dependent activation of Tyk2 requires phosphorylation of positive regulatory tyrosines by another kinase, J. Biol. Chem. 271 (1996) 20494–20500.

Please cite this article in press as: N.R. Leitner et al., Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene, Cytokine (2015), http://dx.doi.org/ 10.1016/j.cyto.2015.10.015